Preparation of penciclovir or famciclovir

ABSTRACT

A process for preparing 2-amino-6-chloropurine or a 2-acylated derivative thereof, comprising reacting guanine or 2,9-diacylguanine with a chlorinating agent, in the presence of methyltriethylammonium chloride as phase transfer catalyst, and thereafter when necessary, removing the 9-acyl group by hydrolysis.

This is a divisional of application Ser. No. 08/409,490 U.S. Pat. No.5,910,589 filed Mar. 21, 1995, which is a continuation of applicationSer. No. 08/094,132 filed Jul. 30, 1993, which is a 371 ofPCT/GB92/00177 filed Jan. 30, 1992.

This invention relates to a process for the preparation of a compounduseful as an intermediate in the preparation of pharmaceuticalcompounds.

The compound 2-amino-6-chloropurine of formula (I): ##STR1## is a usefulintermediate in the preparation of nucleoside analogue antiviral agents,such as penciclovir and famciclovir, described in EP-A-141927(Example 1) and EP-A-182024 (Example 2). The intermediate is9-substituted with an appropriate side chain precursor, followed byconversion of the 6-chloro moiety to a hydroxy (a guanine) or hydrogen(a 2-aminopurine).

EP-A-203685 (Beecham Group p.l.c.) describes a process for preparing acompound of formula (I) as hereinbefore defined, which process comprisesreacting guanine with a chlorinating agent in the presence of a phasetransfer catalyst containing chloride ions. EP-A-433846 (HoechstAktiengesellschaft) describes a corresponding process for preparing the2-acylated derivative, involving chlorination of 2,9-diacylguanine andsubsequent removal of the 9-acyl group by hydrolysis.

The reaction is preferably carried out in a polar inert organic solventsuch as acetonitrile, tetrahydrofuran, dioxan, nitromethane, diglyme ordimethoxyethane. Acetonitrile is highly preferred.

Suitable phase transfer catalysts include tetrasubstituted ammoniumchlorides. Examples of ammonium substituents include C₂₋₁₂ alkyl,usually C₂₋₄ alkyl, or phenyl or benzyl. Other possible phase transfercatalysts include tetra-substituted phosphonium chlorides whereinexamples of the substitutents are as defined above for ammoniumchlorides. The preferred phase transfer catalyst used wastetraethylammonium chloride.

The phase-transfer catalyst is preferably present in an amount of from 1to 3 equivalents of the compound of formula (II) and preferably from 1to 2 equivalents.

A preferred chlorinating agent is phosphorus oxychloride.

Preferably the chlorinating agent is present in an amount of from 2-10preferably from 3-6 molar equivalents of the compound of formula (I).

The reaction may be effected in the presence of a weak base, such as atertiary amine, for example N,N-dimethylaniline or diethylaniline. Thebase is usually present in an approximately molar equivalent amount withrespect to the compound of formula (I). Alternatively, a catalyticamount of water may be added to the reaction mixture. When acetonitrileis the solvent, added base is not necessary.

The reaction is preferably carried out at an elevated temperature offrom 30-100° C., most preferably under reflux and/or withultrasonication at 60-70° C.

Preferably the reaction is allowed to proceed for a period of greaterthan half an hour, usually less than 30 hours.

Surprisingly, we have now discovered that the preferred phase transfercatalyst is methyltriethylammonium chloride (TEMAC).

Accordingly, the present invention provides a process for preparing2-amino-6-chloropurine or a 2-acylated derivative thereof, which processcomprises reacting guanine or a 2,9-diacylated derivative thereof, witha chlorinating agent in the presence of TEMAC, and thereafter whennecessary, removing the 9-acyl group by hydrolysis.

All other aspects of the process are as described in EP-A-203685 andEP-A-433846.

The following examples illustrate the invention.

EXAMPLE 1 2-Amino-6-chloropurine

A mixture of guanine (22.7 g, 0.15 mol), methyltriethylammonium chloride(TEMAC) (45.5 g, 0.3 mol), phosphorus oxychloride (82.6 ml, 0.9 mol) andacetonitrile (67 ml) was heated at 60° C. with stirring for 6 hours andthen cooled to 10° C. The solid material was filtered off and suspendedin water (300 mls). The aqueous mixture was brought to alkaline pH withaqueous sodium hydroxide to achieve dissolution and powdered carbon (6.8g) added. The mixture was stirred for 1 hour and then filtered to removethe carbon. Acetone (72 mls) was added and then the pH reduced to 7 withdilute hydrochloric acid. The product was filtered off, washed withacetone/water (50:50 mixture, 50 mls), water (50 mls), acetone/water(50:50 mixture, 50 mls) and acetone (50 mls) and then dried to give2-amino-6-chloropurine as a cream coloured solid (14.77 g, 54% yield).

EXAMPLE 2 2-Acetylamino-6-chloropurine

Diacetyl guanine (16.0 g, 0.068 moles), TEMAC (20.60 g, 0.136 moles),triethylamine (9.48 mls, 0.068 moles) and acetonitrile (80 mls) wereheated with stirring to 45° C. and stirred for 15 minutes. Phosphorousoxychloride (12.68 mls, 0.136 moles) was added and the temperatureraised to 60° C. The reaction mixture was then stirred at 60-62° C. for21/2 hours. The reaction mixture was then cooled to below 30° C. andadded to sodium hydroxide solution (21.8 g, 0.545 moles, in 400 mlswater) with stirring. The temperature rose to 58° C. The reactionmixture was heated and acetonitrile, triethylamine and water (135 mlstotal) distilled out until the head temperature reached 100° C. theliquor was then cooled and the product filtered off and washed withwater (20 mls). The product was then dried under vacuum at 80° C. for 3days (12.695 g, 88% yield).

What is claimed is:
 1. A process for preparing for penciclovir orfamciclovir, comprising preparing 2-amino-6-chloropurine by reactingguanine with a chlorinating agent in the presence of TEMAC, in asolvent; substituting said 2-amino-6-chloropurine at the 9-position withan appropriate side chain precursor, followed by hydrolysis or reductionof the 6-chloro moiety to hydroxy or hydrogen to provide penciclovir orfamciclovir.
 2. A process according to claim 1 wherein the chlorinatingagent is phosphorus oxychloride.
 3. A process according to claim 1wherein the chlorinating agent is present in an amount of 3 to 6 molarequivalents.
 4. A process according to claim 1 wherein the TEMAC ispresent in an amount of 1 to 2 molar equivalents.
 5. A process accordingto claim 1 wherein the preparation of the 2-amino-chloropurine iscarried out in acetonitrile as solvent.